There are two million individuals in serious trouble with cocaine, and with the exception of alcohol, cocaine still accounts for the largest proportion of admissions for drug treatment. Projects 1 and 2 will test potential medications in controlled outpatient trials. Project 2, on the other hand, will examine in a controlled laboratory setting, the interactive effects of potential medications in experienced cocaine users, who are not seeking treatment, given the opportunity to self-administered cocaine, providing important information about safety, potential clinical utility, and behavioral mechanism of action of potential medications. The medications were selected because of their effects of excitatory amino acids or GABA and because less information is available about them, making controlled laboratory studies essential before their use in an outpatient setting. We will evaluate in non-treatment seeking cocaine abusers, the safety and potential behavioral mechanism of action of 1) acamprosate, a partial agonist at the polyamine site of the NMDA receptor complex; 2) abecarnil, a partial agonist at the GABA-A receptor complex; 3) ACEA- 1021, an antagonist at the glycine binding site of the NMDA receptor; and 4) LY-293558, a selective antagonist at the AMPA subtype of glutamate receptor. We hypothesize that medications that reduce cocaine craving and cocaine choice in the laboratory will be effective at reducing cocaine abuse in treatment-seeking cocaine dependent individuals. We will compare the results of the clinical (Project 2) and laboratory studies (Project 3) of acamprosate and abecarnil. The extent to which the laboratory data predict the clinical data will inform us about the utility of laboratory studies to assess medications that were chosen to disrupt the long-term changes associated with cocaine dependence. The focus on excitatory amino acids and GABA systems, which exert reciprocal effects on the dopamine system, will provide a novel venue for further explorations in the search for pharmacological adjuncts for the treatment of cocaine dependence.